Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC1N(C2C=CC([N+]([O-])=O)=CC=2C#N)C=NC=1>>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:18]=1
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: Cc1cncn1-c1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1

Procedure:
In analogy to example 5a, 2-fluoro-5-nitro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 1 h at 20° C. Aqueous workup afforded a 3.6:1 mixture of the title compound and its regioisomer [2-(5-methyl-imidazol-1-yl)-5-nitro-benzonitrile] as a light brown solid (yield: 69%). MS: m/e=229.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:12])[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:12][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Br:20])=[CH:22][CH:23]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(F)cn1N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)cn1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-amino-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.18 g, 6.88 mmol) in dichloromethane (14 ml) is added triethylamine (3.34 ml, 24.1 mmol). Then 4-bromobenzoyl chloride (3.02 g, 13.8 mmol) is added in portions. The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic layer is washed with 1 N HCl, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-(4-bromo-benzoylamino)-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester as white solid; HPLC/MS 2.78 min (B), [M+H] 355/357.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.ClC[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].O.[CH3:26]S(C)=O>C1CCCCC1.C(OCC)(=O)C>[NH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH3:3])[N:9]([CH2:26][C:18]2[CH:17]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[N:8]=1
Reactant: COc1cccc2[nH]nc(N)c12
Reactant: N#Cc1cccc(CCl)c1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: O
Product: COc1cccc2c1c(N)nn2Cc1ccccc1C#N
Reaction time: 0.33 h
Yield: 59 %

Procedure:
To a solution of ground potassium hydroxide (6.75 g, 120 mmol) in DMSO (300 mL) at room temperature under nitrogen was added 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (7.85 g, 48.1 mmol), and this gave a deep red solution. After 5 minutes 3-(chloromethyl)benzonitrile (8.84 g, 58.3 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes and then poured into water (500 mL), forming an emulsion. This was extracted using chloroform (3×500 mL). The combined organic solutions were washed with water (400 mL) and passed through a hydrophobic frit. The solvent was removed in vacuo, the residue was applied to a 340 g silica cartridge, and eluted with a gradient of 0-100% ethyl acetate in cyclohexane over 8CV. This gave an orange solid which was treated with ethyl acetate (10 mL) and cyclohexane (90 mL). The solid was collected by filtration and washed with cyclohexane (50 mL). The solid was dried in vacuo to give the title compound (7.89 g, 59%) as a pale orange solid. LCMS (System A) RT=0.93 min, ES+ve m/z 279 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:12](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:13].O1CCC[CH2:35]1>>[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:1]=[CH:2]/[C:12]#[N:13])[N:9]=1)(=[O:11])[CH3:35]
Reactant: CC(=O)c1cccc(C=O)n1
Reactant: C1CCOC1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)c1cccc(/C=C/C#N)n1
Reaction time: 6 h

Procedure:
A mixture of 6-acetyl-2-pyridinecarbaldehyde (0.5 g) and cyanomethylenetriphenylphosphorane (1.5 g) in tetrahydrofuran (5 ml) was stirred for 6 hours and the mixture was evaporated in vacuo. The residue was separated and purified by column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (4:1, V/V). The eluted fast fractions containing the desired product were collected and evaporated in vacuo to give 2-acetyl-6-[2-(E)-cyanovinyl]pyridine (0.18 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([NH:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:29]>>[ClH:29].[NH2:13][CH2:12][CH2:11][NH:10][C:8]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncccc1Br
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1ncccc1Br

Procedure:
3.2 g of t-butyl [2-(3-bromopyridine-2-carboxamido)ethyl]carbamate were heated to reflux for 4 hours with 3.5 ml of methylene chloride and 3.5 ml of trifluoroacetic acid. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol and the solution was treated with an equimolar amount of ethanolic hydrochloric acid. The hydrochloride was recrystallized from methanol/ether, whereby there was obtained N-(2-aminoethyl)-3-bromopyridine-2-carboxamide hydrochloride as white crystals, m.p. 279°.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:15][S:16][CH3:17].[OH-].[Na+].CC(OC)(C)C>O>[CH2:1]([O:8][C:9]([NH:12][CH:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSCCC(N)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CSCCC(NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
51 ml benzyloxycarbonyl chloride was dripped into a solution of 50 g (0.34 mole) DL-methionine amide in 200 ml water at 5-20° C., during which the pH was maintained at 7-9 with sodium hydroxide solution. A slimy precipitate formed immediately which became finely crystalline upon the addition of 200 ml MTBE. After the end of the addition the mixture was agitated 30 min further at room temperature. The precipitated, colorless crystals were then filtered off, washed with a little MTBE and recrystallized out of 700 ml toluene. After filtering off, washing with toluene and drying, 67 g (69%) Nαbenzyloxycarbonyl-DL-methionine amide with a melting point of 120-122° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:8][CH:9]=[CH2:10])=[N:4][CH:3]=1.C[N+]1([O-])CC[O:26]CC1.C1COCC1.[OH2:35]>S([O-])([O-])(=O)=S.[Na+].[Na+].[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[S:6][C:5]([CH:7]([C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH2:8][CH:9]([OH:26])[CH2:10][OH:35])=[N:4][CH:3]=1
Reactant: O
Reactant: C=CCC(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)OCC)CC1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(CC(O)CO)c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)but-3-en-1-yl]cyclohexanecarboxylate (40 mg, 0.107 mmol), 4-methylmorpholine N-oxide (14 mg, 0.120 mmol), THF (0.8 ml), water (0.4 ml) and osmium tetroxide (0.2 ml, 0.025 mmol). The mixture was stirred at room temperature for 15 min. The mixture was diluted with sodium thiosulfate and extracted with EtOAc. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (0-100% EtOAc in hexane) to afford ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-3,4-dihydroxybutyl]cyclohexanecarboxylate. MS ESI calc'd. for C16H24BrNO4S [M+H]+ 406, 408. found 406, 408. 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 4.08 (q, J=7.1, 2H), 3.70-2.93 (m, 3H), 2.60-2.42 (m, 1H), 2.25-2.06 (m, 1H), 2.06-1.51 (m, 7H), 1.51-1.30 (m, 2H), 1.22 (t, J=7.1, 3H), 1.14-0.92 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32](O)=[O:33])=[N:27]1.S(Cl)(Cl)=O>CN(C)C=O.CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:32]([C:28]5[C:29]([CH3:31])=[CH:30][N:26]([CH3:25])[N:27]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cn(C)nc1C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1nn(C)cc1C
Yield: 46.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (323 mg, 1.0 mmol), 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (154 mg, 1.1 mmol) tetrahydrofuran (2.0 mL), N,N-dimethylformamide (1 drop), thionyl chloride (0.08 mL, 1.1 mmol) and N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 203, the title compound (208 mg, 47%) was obtained as pale-yellow crystals.
Reaction SMILES: CN(C)C=O.F[C:7]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=1[CH:9]=O.[SH:17][CH2:18][C:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].[C:28](OCC)(=O)[CH3:29]>O>[CH2:28]([O:20][C:19]([C:18]1[S:17][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=2[CH:9]=1)=[O:21])[CH3:29]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C=O)c(F)c1
Reactant: O=C([O-])CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(OC)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 32.5 mmol) and 2-mercapto-acetate (3.56 mL, 32.5 mmol) was added potassium carbonate (12.1 g, 87.5 mmol). This mixture was stirred at room temperature for 5 hours. The reaction mixture was distributed between ethyl acetate and water. The organic layer was separated followed by washing with water, drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel chromatography (heptane:ethyl acetate=20:1 to 10:1) and NH silica gel chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (6.72 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2Cl.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]1
Reactant: O=C(c1cnc2cc(F)c(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloro-7-fluoroquinolin-3-yl)(cyclopropyl)methanone (350 mg, 1.06 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (270 mg, 1.27 mmol) to afford the desired product (400 mg, 75%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.67 (d, J=8.3 Hz, 1H), 9.22 (s, 1H), 8.32 (d, J=7.3 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H), 4.42 (s, 1H), 3.91 (d, J=8.1 Hz, 1H), 3.52 (s, 1H), 2.75-2.56 (m, 1H), 2.18 (t, J=13.4 Hz, 4H), 1.72-1.62 (m, 1H), 1.59-1.50 (m, 2H), 1.45 (s, 9H), 1.30-1.18 (m, 3H), 1.13-1.01 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[NH:8][C:7](=O)[CH:6]3[CH2:16][CH2:17][CH2:18][CH:5]3[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[NH:8][C:7](=[S:28])[CH:6]3[CH2:16][CH2:17][CH2:18][CH:5]3[C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NC(=O)C1CCCC21
Product: Cc1cc2c(cc1[N+](=O)[O-])NC(=S)C1CCCC21
Yield: 74.7 %

Procedure:
As described for Example 4, 8-methyl-7-nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (60 mg, 0.24 mmol) is reacted with Lawesson's reagent (105 mg, 0.26 mmol) to form 47 mg (75%) of product.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:10]([CH:11]([C:13]2[C:14]([CH3:19])=[N:15][CH:16]=[N:17][CH:18]=2)[OH:12])=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:4].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[CH2:3]([C:5]1[C:10]([CH:11]([C:13]2[C:14]([CH3:19])=[N:15][CH:16]=[N:17][CH:18]=2)[O:12][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:4]
Reactant: CCc1ncncc1C(O)c1cncnc1C
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ncncc1C(OC(=O)C(C)(C)C)c1cncnc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.5 %

Procedure:
To 3.2 mg of oil-free NaH was added 26 mg of 1-(4-ethylpyrimidin-5-yl)-1-(4-methylpyrimidin-5-yl)methanol in 1 ml THF at -30° C., followed by addition of 15 mg of pivaloyl chloride. After warming to room temperature and stirring for 1.5 hours, the reaction was quenched with 1 ml H2O and extracted with ether (3 times). The combined organics were washed with brine, dried (MgSO4) and evaporated to yield 30.7 mg of 1-(4-ethylpyrimidin-5-yl)-1-(4-methylpyrimidin-5-yl)-1-trimethylacetoxymethane as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[C:30]([F:33])([F:32])[F:31].N12CCN(CC1)CC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:26]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[C:21]([C:30]([F:33])([F:31])[F:32])[CH:22]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(C(F)(F)F)c2)c(OC)c1
Yield: 32.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (150 mg, 0.611 mmol) prepared in Example 14a, 4-fluoro-3-(trifluoromethyl)benzenesulfonyl chloride (321 mg, 1.22 mmol), 1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0 mL), to yield the title compound (94.7 mg, 33%) as a colorless oil.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>>[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:47][C:36]([C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([C:23]4[CH:22]=[C:21]([N:15]5[C:14](=[O:39])[C:13]6[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=6)[C:16]5=[O:20])[CH:26]=[CH:25][CH:24]=4)[O:28][C:29]=3[CH:35]=2)=[O:37])=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2ccc3nc(-c4cccc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)c4)oc3c2)cc1

Procedure:
Prepared by the method of Example 76 g), from 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) and 4-methoxybenzylamine (19 mg, 0.14 mmol) the title compound was obtained (22 mg, 45%). 1H NMR (DMSO) δ 9.20(t, 1H), 8.43(dd, 1H), 8.36(m, 2H), 8.30(m, 2H), 8.09(d, 1H), 7.99(dd, 1H), 7.91(d, 1H), 7.82–7.89(m, 2H), 7.28(d, 2H), 6.89(d, 2H), 4.45(d, 2H), 3.73(s, 3H). MS 545.9 m/z (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=O)[NH:6][CH:7]=[N:8][C:9]=1[CH3:10])[CH2:2][CH3:3].O=P(Cl)(Cl)[Cl:14]>>[CH2:1]([C:4]1[C:5]([Cl:14])=[N:6][CH:7]=[N:8][C:9]=1[CH3:10])[CH2:2][CH3:3]
Reactant: CCCc1c(C)nc[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1c(C)ncnc1Cl
Temperature: 85 °C

Procedure:
A mixture of 5-propyl-6-methyl-pyrimidin4-one (10 mmol) and POCl3 (25 ml) is heated at 85° C. for 4 hours. The solvent is removed in vacuo and EtOAc (30 ml) and water (30 ml) are added to the residue. NaHCO3 is carefully added until the pH of aqueous layer is greater than 7. The layers are separated and the aqueous layer is extracted with EtOAc (2×30 ml). The combined extracts are washed with brine (50 ml), dried (Na2SO4), and evaporated. Flash column purification of the residue with 6:1 EtOAc:hexane provides the title product as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])=[CH:6][CH:5]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[N:3]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[CH:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17]
Reactant: Nc1ccc(Nc2ccc(C(=O)c3c(F)cccc3F)c(N)n2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc(NS(=O)(=O)c3ccccc3)cc2)ccc1C(=O)c1c(F)cccc1F
Yield: 73.5 %

Procedure:
A solution of Compound 17 (5.8 mg, 0.017 mmol), benzenesulfonyl chloride (2.38 μL, 0.019 mmol), triethylamine (2.9 μL, 0.021 mmol) in THF (0.2 mL) and methylene chloride (0.2 mL) was stirred at rt for about 2 hours. The resultant mixture was then separated by chromatography (on silica gel, eluting with 1:1 ethyl acetate:hexane) to give Compound 19 (6 mg, 73% yield).
Reaction SMILES: [O:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Br:8])[CH:2]([CH3:4])[CH3:3].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br-:8].[CH:2]([O:1][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:4])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)Oc1ccccc1CBr
Product: CC(C)Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
2-Isopropoxybenzyltriphenylphosphonium bromide was prepared from 2-isopropoxylbenzyl bromide according to the method used in Example 76, except that 1.3 equivalents of triphenylphosphine was used. 2-Isopropoxybenzyltriphenylphosphonium bromide was isolated as a white solid. Yield (11.2 g, 99%): 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.89 (m, 3H), 7.70 (dt, J=8.0, 3.2 Hz, 6H), 7.54-7.59 (m, 6H), 7.23-7.28 (m, 1H), 6.91 (dt, J=7.6, 2.0 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.74 (t, J=7.6 Hz, 1H), 4.87 (d, J=14.4 Hz, 2H), 4.29 (quint, J=6.0 Hz, 1H), 0.91 (d, J=6.0 Hz, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.O[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:30]=1.O>O1CCOCC1>[Br:20][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CSc1nccc(O)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CSc1nccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 52.5 g (0.20 mol) of triphenylphosphine are initially charged in 600 ml of dioxane, and 35.6 g (0.20 mol) of N-bromosuccinimide are added a little at a time, with cooling. The mixture is stirred at RT for 30 min. 8.6 g (0.04 mol) of ethyl [(4-hydroxy-2-pyrimidinyl)thio]acetate are then added and the mixture is heated at reflux for 45 min. A total of 2 l of water are added to the mixture, which is then extracted 3× with in each case 300 ml of methyl tert-butyl ketone. The organic phase is washed 2× with water and 1× with concentrated NaCl solution, dried over magnesium sulphate and concentrated. The residue is stirred in 60 ml of methyl tert-butyl ketone and filtered off. The mother liquor is concentrated and the residue is purified by silica gel chromatography (dichloromethane).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.O[CH2:37][C:38]1([CH:42]([OH:44])[CH3:43])[CH2:41][CH2:40][CH2:39]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:43][CH:42]1[O:44][C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35][CH2:37][C:38]21[CH2:41][CH2:40][CH2:39]2
Reactant: CC(O)C1(CO)CCC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC2(CCC2)C(C)O3)c2ncnn12
Temperature: 25 °C

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (12.67 g), 1-[1-(hydroxymethyl)cyclobutyl]ethanol (4.26 g), p-toluenesulfonic acid hydrate (0.57 g) and toluene (300 mL) was refluxed with heating for 5 hr while dehydrating with a Dean-Stark trap. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (13.64 g, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@:12](O)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]([F:16])([F:15])[F:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>C(OCC)C>[CH2:1]([O:8][C:9](/[N:11]=[C:12](/[C:13]([F:14])([F:16])[F:15])\[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@](O)(NC(=O)OCc1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)/C(=N\C(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-hydroxyalaninate (2690 g, 8.39 mol) in diethyl ether (18 L) under an atmosphere of nitrogen was added dropwise 2,2,2-trifluoroacetyl 2,2,2-trifluoroacetate (1937 g, 9.22 mol) at 0° C. followed by the addition of pyridine dropwise (1457 g, 18.44 mol) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 6 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford ethyl (2E)-2-{[(benzyloxy)carbonyl]imino}-3,3,3-trifluoropropanoate.